Inhibition of myostatin and proteases to accelerate muscular rehabilitation following disuse atrophy and spinal cord injury Project I will focus on the identification of targets for novel pharnnacological interventions, as well as evaluate existing drugs, with the goal of ameliorating skeletal muscle atrophy, and/or increase the rate of rehabilitation, following either disuse/unloading or spinal cord injury. Specifically, this project will assess the efficacy of protease inhibition on the prevention of muscle atrophy during disuse and following spinal cord injury. The project will also examine the possible effect of myostatin inhibition on preventing muscle loss following spinal cord injury, and its effect on accelerating muscle size and strength following reloading. The project will also assess possible synergistic effects between myostatin and IGF-I signaling. There are a number of potential protease targets during skeletal muscle atrophy that are up-regulated during unloading, including calpain, cathepsins, and specific arms of the ubiquitin-proteosome pathway. These pathways will be inhibited with specific drugs, alone and in combination. Myostatin is increased during muscle disuse. However the significance of this on atrophy is unclear, as is the possible effect on rehabilitation following reloading of the muscle. We will observe the effect of systemic delivery of myostatin inhibitors (produced via AAV delivery to the liver) on the process of atrophy and on muscle mass and strength increase following reloading. The long-term goal of this project is to develop novel interventional strategies that minimize skeletal muscle atrophy and promote muscle regeneration. Drugs that modulate the pathways validated by this project would be used in conjunction with existing rehabilitation interventions to facilitate the recovery of muscle function and functional ability. This interplay between pharmacological interventions and rehabilitation will be evaluated in mice undergoing reloading following hindlimb suspension and in rats following spinal cord injury and locomotor training. RELEVANCE (See instructions): Loss of skeletal muscle mass and strength occurs during periods of disuse (e.g. chronic bed rest or limb immobilization), and also occurs following spinal cord injury. This project seeks to identify drugs and/or drug targets to slow this loss of muscle, enabling more rapid and complete rehabilitation following either a period of disuse or following spinal cord injury.